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Publication number
WO2023210026A1
WO2023210026A1 PCT/JP2022/020301 JP2022020301W WO2023210026A1 WO 2023210026 A1 WO2023210026 A1 WO 2023210026A1 JP 2022020301 W JP2022020301 W JP 2022020301W WO 2023210026 A1 WO2023210026 A1 WO 2023210026A1
Authority
WO
WIPO (PCT)
Prior art keywords
aptamer
electrode
pillar
cells
sensor
Prior art date
Application number
PCT/JP2022/020301
Other languages
English (en)
Inventor
Soo Hyeon Kim
Shuo Li
Teruo Fujii
Nicolas Clement
Original Assignee
The University Of Tokyo
Centre National De La Recherche Scientifique
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of Tokyo, Centre National De La Recherche Scientifique filed Critical The University Of Tokyo
Priority to PCT/JP2022/020301 priority Critical patent/WO2023210026A1/fr
Publication of WO2023210026A1 publication Critical patent/WO2023210026A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N15/0656—Investigating concentration of particle suspensions using electric, e.g. electrostatic methods or magnetic methods
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N15/0606—Investigating concentration of particle suspensions by collecting particles on a support
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5308—Immunoassay; Biospecific binding assay; Materials therefor for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/01—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials specially adapted for biological cells, e.g. blood cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/1023—Microstructural devices for non-optical measurement
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/1031—Investigating individual particles by measuring electrical or magnetic effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology

Definitions

  • the present invention relates to sensor.
  • Cancer is still one of the main pathologies with high probability of negative prognostic (death) in humans.
  • CTCs rare circulating tumor cells
  • electrochemical sensors are typically based on physical-chemical effects such as fluorescence, chemiluminescence, magnetic beads, calorimetry profiling or electrochemistry.
  • electrochemical sensors provide attractive means for easy operation, high sensitivity, and portability. Additionally, they can benefit from ultimate scaling, either using redox-cycling or high-frequency signal amplification effects, as illustrated by the successful launch of ECsens startup for detecting individual biomarker particles specifically.
  • the present invention has been made in view of the above problems, and an object of the present invention is to provide a redox-labelled sensor being able to improve signal to noise ratio.
  • the present invention has been made based on the above findings, and the gist is as follows.
  • a sensor comprising: a substrate; an electrode formed on at least a surface of the substrate; a pillar formed on a surface of the electrode; and an aptamer formed on the surface of the electrode, wherein a length of the aptamer in hairpin configuration is shorter than a height of the pillar in direction perpendicular to the surface of the electrode.
  • aptamer is selected from the group consisting of a nucleic acid aptamer, a peptide aptamer, a protein aptamer, and a peptide nucleic acid.
  • FIG. 1(a) is schematic representation of the sensor composed of nanopillars suspending non-target cells according to embodiment of the present invention.
  • FIG. 1(b) is schematic representation of the sensor composed of nanopillars suspending target cells according to embodiment of the present invention.
  • FIG. 1(c) is Atomic Force Microscope (AFM) image and cross section of the HSQ nanopillars according to Example of the present invention.
  • AFM Atomic Force Microscope
  • FIG. 1(d) is schematic representation of the Cyclic Voltammetry (CV/CVs) the embodiment of the present invention.
  • FIG. 2(a) is graph showing results of CVs of a sensor measured until 14 days according to Example of the present invention.
  • FIG. 2(b) is graph showing results of CVs of 10 different sensor with same fabrication condition according to Example of the present invention.
  • FIG. 3(a) is graph showing AFM cross section and CV according to Example of the present invention.
  • FIG. 3(b) is graph showing AFM cross section and CV according to Example of the present invention.
  • FIG. 4 is figure showing schematic representation of the sensor and CVs according to Example of the present invention.
  • FIG. 5(a) is graph showing CV according to Example of the present invention.
  • FIG. 5(b) is graph showing CV peaks (I pe ak) plotted as a function of cells concentration according to Example of the present invention.
  • FIG. 6(a) is graph showing hydrogen bonds energy estimated from MD simulation of tethered SYL3C aptamers without confinement, and under 5nm confinement according to Example of the present invention.
  • FIG. 6(b) is graph showing I pea k plotted as a function of temperature for unconfined SYL3C, confined SYL3C with Ramos cells, and confined SYL3C with Capan-2 cells.
  • FIG. 7 is graph showing results of stability test for CVs of the sensor with only Aptamer modified with Ferrocene (Apt-Fc) molecules obtained in 1.5 h according to Example of the present invention.
  • FIG. 8 is fluorescent image to show the capan-2 cells clusters on the surface of our sensor after incubation according to Example of the present invention.
  • FIG. 9(a) is graph showing CVs of Apt-Fc under confinement with Ramos cells according to Example of the present invention.
  • FIG. 9(b) is graph showing CVs of Apt-Fc unconfmed according to Example of the present invention.
  • FIG. 9(c) is graph showing CVs of Apt-Fc under confinement with Capan-2 cells according to Example of the present invention.
  • FIG. 10 is images showing the cell concentration and cell size.
  • Coupled and “connected”, which are utilized herein, are defined as follows.
  • the term “connected” is used to describe a direct connection between two circuit elements, for example, by way of a metal line formed in accordance with normal integrated circuit fabrication techniques.
  • the term “coupled” is used to describe either a direct connection or an indirect connection between two circuit elements.
  • two coupled elements may be directly coupled by way of a metal line, or indirectly connected by way of an intervening circuit element (e.g., a capacitor, resistor, or by way of the source/drain terminals of a transistor).
  • circuit means either a single component or a multiplicity of components, either active or passive, that are coupled together to provide a desired function.
  • signal means at least one current, voltage, or data signal.
  • the sensor 100 includes: a substrate 200; an electrode 300 being formed on at least a surface of the substrate 200; a pillar 400 being formed on a surface of the electrode 300; and a sensing element 500 formed on the surface of the electrode, and including an aptamer 510, wherein a length of the aptamer 510 is shorter than a height of the pillar 400 in direction perpendicular to the surface of the electrode 300.
  • FIG. 1(a) is schematic representation of the sensor composed of nanopillars suspending non-target cell according to embodiment of the present invention.
  • the sensor 100 includes the substrate 200.
  • the substrate 100 at least has one surface (A).
  • the substrate 100 may be plate shape or sheet shape.
  • a material of the substrate 100 may be at least one or more selected from the group consisting of a dielectric material, a semiconductor material, and conductor material.
  • the substrate 100 is semiconductor material.
  • circuits can be from on the surface (A) of the substrate 100 and buried in the substrate 100. Thereby, the sensor 100 can be more compact.
  • the substrate 100 may be flexible substrate 100.
  • the sensor 100 includes the electrode 300.
  • the electrode 300 is formed on the surface (A) of the substrate 200.
  • the electrode 300 has one surface (A) that is different from a surface being in touch with the surface (B) of the substrate 200.
  • the electrode 300 may be plate shape or sheet shape.
  • the electrode 300 is one or more selected from the group consisting of a metal, a semiconductor, and a carbon material.
  • the electrode 300 is Au.
  • the sensor 100 includes the pillar 400.
  • the pillar 400 is formed on the surface (B) of the electrode 300.
  • the pillar 400 is for supporting a cell. Thereby, the pillar 400 ensures that the cell is too close with the sensing element 500. Thus, noise by cells gravity or cells stickiness can be further decreased. Therefore, signal to noise ratio can be further improved.
  • the pillar 400 may include a surface being parallel to the surface of the electrode and being placed apart from the surface of the electrode 300.
  • a pillar array may be form on the surface (B) of the electrode 300.
  • the pillar array may be a regular array.
  • a height of the pillar may be 5 nm to 40 nm. Thereby, noise by cells gravity or cells stickiness can be further decreased.
  • the diameter between the pillars may be 200 nm or more. Thereby, penetration of pillars in the cell membrane can be avoided.
  • the pillar may be made of a dielectric material.
  • the pillar 400 is hydrogen-silsesquioxane (HSQ) nanopillars.
  • the sensor 100 includes the sensing element 500.
  • the sensing element 500 may include the aptamer 510, and a redox label 520.
  • the sensing element 500 is formed on the surface (B) of the electrode 300. That is, the sensing element 500 is formed on the same surface of the electrode 300 as the pillar 400.
  • the length of the aptamer 510 is shorter than the height of the pillar in direction perpendicular to the surface of the electrode.
  • the aptamer 510 is oligonucleotide or peptide molecules that bind to a specific target molecule.
  • the aptamer 510 can be one or more selected from the group consisting of a nucleic acid aptamer, a peptide aptamer, a protein aptamer, and a peptide nucleic acid.
  • the nucleic acid aptamer can be a DNA aptamer or RNA aptamer.
  • the aptamer 510 is DNA aptamer.
  • the length of the aptamer 510 may be 10 nm to 30 nm.
  • the redox label 520 may be attached to the aptamer 510.
  • a type of the redox label 520 is not limited. In FIG. 1(a), the redox label 520 is ferrocene.
  • the pillar 400 ensures that the cell is too close with the sensing element 500, noise by cells gravity or cells stickiness can be further decreased. Therefore, signal to noise ratio can be further improved.
  • FIG. 1(a) is schematic representation of the sensor composed of nanopillars suspending non-target cells according to embodiment of the present invention. It is composed of: 1) a gold working electrode; 2) an active monolayer, composed of tethered Ferrocene (Fc)-labelled DNA aptamers (the experimentally identified SYL3C) deposited on a gold surface, for the recognition of the Epithelial Cell Adhesion Molecule (EpCAM), also including oligoethylene-glycol molecules (OEG) to avoid non-specific adsorption; and 3) a regular array of hydrogen-silsesquioxane (HSQ) nanopillars.
  • the regular array of hydrogen-silsesquioxane (HSQ) nanopillars is fabricated by high-speed electron-beam (e-beam) lithography, used to improve the signal to noise ratio of e-DNA cytosensors.
  • the HSQ solution is cross-linked to form a SiOx network structure after the exposure, which provides a chemically stable, flat, and biocompatible pattern.
  • the diameter of 200 nm for the pillars has been chosen to avoid penetration of pillars in the cell membrane. Pillars pitch and height depend on cell deformation between pillars, and the length of the DNA aptamers dispersed on the surface between the pillars.
  • the 500 nm pitch was chosen on the basis of a theoretical cell adhesion/deformation phase diagram as well as high yield fabrication process, as small pillar height requires a dense configuration.
  • 1(c) presents the optimized nanopillars configuration with 200 nm diameter, 20 nm height and 500 nm pitch aiming to keep cells at a distance z sap of few nanometers above the surface, small enough to enable interaction of SYL3C aptamers with EpCAMs (FIG.1 (b)).
  • FIGs. 1(a), and 1(b) depict how the aptamer Brownian motion affects the charge transfer between Fc and the electrode.
  • Typical Cyclic Voltammetry (CV) curves are shown in FIG. 1(d).
  • CV Cyclic Voltammetry
  • the last tunable parameter is the pillars height that can be controlled precisely with HSQ.
  • FIGs.3(a), 3(b) and 4(a) show CVs obtained for 7.1, 17.6 and 20 nm pillars height, respectively, while FIG.4(b) shows CVs without any pillars, both in the absence and presence of Ramos cells. While the CV peak (I pea k) is unaffected by the presence of Ramos cells for 20 nm thick pillars, I pea k is decreased with smaller pillar heights, suggesting that cells are “pushing” on the aptamer layer.
  • FIG.6a shows the hydrogen bond energy histogram for tethered SYL3C at different temperatures in the absence/presence of a 5 nm confinement. This energy is related to the number of base pairs formed by the single-strand DNA, and therefore to the various hairpin configurations.
  • the unconfined tethered SYL3C shows three main peaks at 20 °C, whereas only low energy peaks are observed above 40 °C, as expected from the 3 and 1-2 hairpins SYL3C configurations (FIG.6a).
  • I pea k remains at its maximum value because all Fc, associated with aptamer Brownian motion in confined space, have a chance to exchange electrons to the bottom electrode. In other words, I pea k is only related to the number of aptamers on the surface. In contrast, I pea k decreases with temperature for unconfined SYL3C that can be associated with a decreased probability of electron transfer to the bottom electrode (the unconfined single-hairpin configuration extends Fc-surface distance).
  • I pea k decreases substantially with the temperature in the presence of Capan-2 cells. This is related to the mechanism illustrated in FIG. lb with blocked electron transfer due to specific molecular recognition with aptamer folded DNA, Fc remaining close to the cell interface during recognition and cannot reach the bottom electrode. Therefore, I pea k decrease can be related statistically to the percentage of aptamers interacting with the cell, a process that is thermally activated. Discussion on “cell gravity” signal to noise and temperature effects the present device with suspended cells improves signal to noise ratio as it suppresses the parasitic signal arising from non-target cells (FIGs. 4a, b), clearly pointing out what we can call a “cell gravity” issue. Interestingly, previously reported electrochemical cytosensors (beyond e-DNA sensors) were typically based on a more complex architecture involving several self-assembly steps and nanoparticles.
  • nanoparticles once on the surface, are playing a role analogue to the HSQ nanopillars introduced here.
  • the nanopillar approach has the merit to simplify the assembly process, to control perfectly z gap , and to be compatible with an aggressive downscaling/integration with many nanoelectrodes. It is also compatible with other nanoelectrochemical sensing approach including the one introduced by ECsens, so far based on biological systems smaller than 2 microns. Future versions of the device will be developed in multiple electrode configurations, thus enabling statistical analysis at the single-cell level, exploiting our single-cell trapping lab-on-chip.
  • the actual limit of detection is the nonfaradic capacitance arising from the sensing nanolayer, that is proportional to the active area.
  • 13 cells correspond to about 1/1000 of the active area in the present experiment
  • the use of sensing area matching exactly to a single-cell with microwells should enable to get high signal to noise ratio at the single-cell level.
  • the absolute I pea k value is expected to be in the tens of pA for a single cell, which could be measured with commercial equipment.
  • the recent breakthrough in electrochemistry instrumentation allowing CVs at the aA level would be directly beneficial to the present sensing approach, allowing sub-cellular (and potentially single-molecule) studies with nanoelectrodes in the 10 nm-range.
  • a second advantage is related to the temperature dependence associated with the confinement effect. These devices aim to be implemented at the single-cell level, providing statistical distributions related to target and non-target cells populations.
  • the difference in signal AI pea k is increasing significantly with temperature as I pea k related to non-target cells doesn’t depend on temperature (as opposed to unconfined aptamers).
  • FIG.6b illustrates this with a clear change in AI pea k observed at 30 °C, with cells simply inserted in a microfluidic channel without any prior incubation.
  • a novel nano-electrochemical biosensor that uses nanopillar arrays to efficiently suppress the issue of cell gravity effect.
  • the stability and efficiency of this device is illustrated for the detection of EpCAM expressed in pancreatic cancer cells. Selectivity and sensitivity are illustrated over 3 orders of magnitude.
  • the next device generation will be focusing on single-cell and potentially sub-cellular or single-molecule measurements, thereby offering unprecedented statistical analysis for the detection of rare cells such as CTCs.
  • Molecular dynamics and experimental data presented here suggest that confinement significantly improves signal to noise ratio and affects aptamers melting temperature. Such an effect is a precious degree of freedom to optimize molecular interactions at near room temperature.
  • the Silicon wafer deposited with 20 nm gold/2 nm Ti was cleaned in Acetone with sonication for 5 min, followed by rinsing with Isopropyl alcohol, deionized water and drying with nitrogen gas.
  • the cleaned chip was immersed in the freshly prepared solution of 1 mM OEG-SH in pure ethanol (containing an ethylene glycol repeat unit HS(CH2)B(OCH2CH2)6OCH2COOH, purchased from Prochimia) for 1 h and cleaned with ethanol, then immersed in 1 pM ssDNA-Fc solution, i.e., thiolated SYL3C aptamer dissolved in 0.5 M potassium phosphate solution (pH 8) for 2 h to obtain the mixed self-assembled monolayer surface.
  • 1 mM OEG-SH in pure ethanol (containing an ethylene glycol repeat unit HS(CH2)B(OCH2CH2)6OCH2COOH, purchased from Prochimia) for 1 h and cleaned with ethanol, then immersed in 1 pM ssDNA-Fc solution, i.e., thiolated SYL3C aptamer dissolved in 0.5 M potassium phosphate solution (pH 8) for 2 h to obtain
  • the aptamer sequence was as follows: ferrocene-5'-CAC TAC AGA GGT TGC GTC TGT CCC ACG TTG TCA TGG GGG GTT GGC CTG-(CH 2 ) 3 -3'-SH (purchased from Biomers).
  • the density of the probes was estimated to be about 2 x 10 13 aptamers/cm 2 from the CV curves after background subtraction.
  • the OEG or PEG backfilling approach is known to drastically reduce biofouling and thus nonspecific protein adsorption.
  • the sample was cleaned with a solution of 0.05% Tween 20 for 10 s before use.
  • Hydrogen silsesquioxane (HSQ, Dow Coming XR-1541) negative electron beam (e-beam) resist is used to fabricate the nanopillars by using e-beam lithography; in this work the Advantest F7000s-VD02 e-beam machine is used.
  • the HSQ resist in a carrier solvent of MIBK was spin-coated on the Au/Ti/Si subtracted with acceleration 5000 rpm for 60 s and then baking at 150 °C for 2 min.
  • the cured sample was then loaded in the e-beam machine and was exposed with a dose of 500 pC/cm 2 by using the on the fly (OTF) mode.
  • the exposed sample was finally immersed in the alkali developer NMD-3 (TMAH 2.38%) for 5 min and then cured at 150 °C for 5 min to obtain the desired nanopillar array.
  • TMAH 2.38% alkali developer NMD-3
  • Capan-2 Human Pancreas Adenocarcinoma cell line
  • Ramos cells Backitt lymphoma cell line
  • Capan-2 and Ramos cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 100 mg/mL penicillin-streptomycin) in a 5% CO2 atmosphere at 37 °C.
  • FBS fetal bovine serum
  • the cells were collected and separated from the medium by centrifugation at 1000 rpm, 4 °C for 5 min, and then were resuspended in a sterile PBS solution (pH 7.1), to obtain a homogeneous cell suspension.
  • the cell suspension was prepared just before incubating with device.
  • the cell number and cell size ( Figure 10) were determined using a Petro ff-Hausser Vcell counting chamber.
  • the coaxial stacking term captures stacking interactions between bases that are not immediate neighbors along the backbone of a strand. Hydrogen-bonding interactions are possible only between complementary, Crick- Watson (A-T and C-G) base pairs, with the additional condition of approximate antialignment of the phosphodiester linkage, which leads to the formation of double helical structures. Bases and backbones also have excluded volume interactions, as well as backbones interactions.

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Abstract

Capteur comprenant : un substrat ; une électrode étant formée sur au moins une surface du substrat ; un pilier étant formé sur une surface de l'électrode ; et un élément de détection formé sur la surface de l'électrode, et comprenant un aptamère, une longueur de l'aptamère étant plus courte qu'une hauteur du pilier dans une direction perpendiculaire à la surface de l'électrode.
PCT/JP2022/020301 2022-04-26 2022-04-26 Capteur WO2023210026A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012037397A (ja) * 2010-08-06 2012-02-23 Canon Inc センサ素子製造方法、センサ素子及び検出方法
US20180100188A1 (en) * 2016-10-07 2018-04-12 Boehringer Ingelheim Vetmedica Gmbh Analysis system and method for testing a sample
US20190265236A1 (en) * 2016-03-30 2019-08-29 Waqas Khalid Nanostructure array based sensors for electrochemical sensing, capacitive sensing and field-emission sensing
US20200072825A1 (en) * 2016-12-09 2020-03-05 Digital Sensing Limited Electrochemical sensors and methods of use thereof
US20200087810A1 (en) * 2016-12-09 2020-03-19 Manufacturing Systems Limited Apparatus and methods for controlled electrochemical surface modification

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012037397A (ja) * 2010-08-06 2012-02-23 Canon Inc センサ素子製造方法、センサ素子及び検出方法
US20190265236A1 (en) * 2016-03-30 2019-08-29 Waqas Khalid Nanostructure array based sensors for electrochemical sensing, capacitive sensing and field-emission sensing
US20180100188A1 (en) * 2016-10-07 2018-04-12 Boehringer Ingelheim Vetmedica Gmbh Analysis system and method for testing a sample
US20200072825A1 (en) * 2016-12-09 2020-03-05 Digital Sensing Limited Electrochemical sensors and methods of use thereof
US20200087810A1 (en) * 2016-12-09 2020-03-19 Manufacturing Systems Limited Apparatus and methods for controlled electrochemical surface modification

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